rs137852557

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 17P and 4B. PM1PM5PP2PP3_StrongPP5_Very_StrongBS2

The NM_000451.4(SHOX):c.502C>T(p.Arg168Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. 3 hem. )

Consequence

SHOX
NM_000451.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.883

Publications

0 publications found

Variant links:

Genes affected

SHOX (HGNC:10853): (SHOX homeobox) This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

SHOX Gene-Disease associations (from GenCC):

Leri-Weill dyschondrosteosis
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Langer mesomelic dysplasia
Inheritance: Unknown, XL, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
SHOX-related short stature
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SHOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000451.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-640837-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3344829.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.53811 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, SHOX-related short stature.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant X-640836-C-T is Pathogenic according to our data. Variant chrX-640836-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4 link	c.502C>T	p.Arg168Trp	missense_variant	Exon 3 of 5	ENST00000686671.1	NP_000442.1	O15266-1A0A024R385
SHOX	NM_006883.2 link	c.502C>T	p.Arg168Trp	missense_variant	Exon 4 of 6		NP_006874.1	O15266-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHOX	ENST00000686671.1 link	c.502C>T	p.Arg168Trp	missense_variant	Exon 3 of 5		NM_000451.4	ENSP00000508521.1	O15266-1
SHOX	ENST00000381575.6 link	c.502C>T	p.Arg168Trp	missense_variant	Exon 3 of 5	1		ENSP00000370987.1	O15266-2
SHOX	ENST00000381578.6 link	c.502C>T	p.Arg168Trp	missense_variant	Exon 4 of 6	5		ENSP00000370990.1	O15266-1
SHOX	ENST00000334060.8 link	c.502C>T	p.Arg168Trp	missense_variant	Exon 4 of 6	5		ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251180

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111840

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leri-Weill dyschondrosteosis

Pathogenic:2

Apr 29, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SHOX c.502C>T (p.Arg168Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251180 control chromosomes. c.502C>T has been observed in multiple individuals affected with SHOX-related disorders, including heterozygous female individuals with Leri-Weill Dyschondrosteosis or short stature and in at least one male with Langer Mesomelic Dysplasia who had a pseudoautosomal microdeletion involving SHOX on the other allele, and it has been found to segregate with these phenotypes within related individuals (e.g. Ogata_2002, Binder_2004). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15356038, 11889214). ClinVar contains an entry for this variant (Variation ID: 9879). Based on the evidence outlined above, the variant was classified as pathogenic for Leri-Weill Dyschondrosteosis, short stature, and Langer Mesomelic Dysplasia. -

Mar 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Langer mesomelic dysplasia syndrome

Pathogenic:1

Mar 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Apr 17, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in individuals with SHOX-related disorders in the published literature (PMID: 23636926, 15356038, 15931687, 11889214); Published functional studies suggest that this variant leads to a loss of DNA binding and reduced ability for homodimer formation (PMID: 15931687); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23636926, 15931687, 15356038, 32932528, 21262861, 11889214) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.70

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;.

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.92

D;D;.

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

4.7

H;H;H

PhyloP100

0.88

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.85

MutPred

0.87

Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);

MVP

1.0

MPC

1.6

ClinPred

0.99

GERP RS

0.30

Varity_R

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs137852557

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over